The history of analgesic and anti-inflammatory medicines started with the use of decocted salicylate-containing plants by ancient Greek and Roman physicians. Willow bark was already used 300 BC for treating fever and pain. Sodium salicylate was introduced in 1875 as an antipyretic. At Bayer in Germany the less corrosive acetylsalicylic acid was synthesized and introduced into medicine in 1899 under the name of aspirin.
The impressive anti-inflammatory, analgesic and antipyretic effects of aspirin prompted researchers to develop a large number of related compounds most of which are organic acids. These compounds, referred to as aspirin-like drugs or nonsteroidal anti-inflammatory drugs (NSAIDs) are a heterogeneous group of substances which have no uniform chemical properties but share the same therapeutic effects as well as unwanted side effects. In 1971 Vane and colleagues have shown that aspirin and other NSAIDs inhibited the synthesis of prostaglandins. Prostaglandins serve many diverse functions throughout the body, with important roles in blood clotting, ovulation, initiation of labor, bone metabolism, nerve growth and development, wound healing, kidney function, blood vessel tone, and immune response (DuBois R. N. et al FASEB J. 1998, 12, 1063). Prostaglandins are produced locally in many different tissue types and have different local actions. PGE2 is generally thought to be the most important pro-inflammatory prostaglandin mediating tissue swelling, fever and hyperalgesia (heightened pain sensitivity). However, other prostanoids may be equally important. Prostacyclin (PGI2), for example, is likely to play an important role in the development of inflammatory pain (K. R. Bley, J. C. Hunter, R. M. Eglen and J. A. M. Smith; 1998, Trends in Pharmacological Science 19, 141–147). Another prostanoid, thromboxane, is produced by platelets and plays a crucial role in thrombotic events. The first enzyme in the prostaglandin synthetic pathway is fatty acid cyclooxygenase, which occurs in two forms, COX-1 and COX-2. COX-1 is constitutively expressed in many cells and tissues such as stomach, kidney and platelets, while COX-2 is induced at sites of injury by exogenous and endogenous inflammatory mediators. Aspirin acetylates serine residues in COX-1 and COX-2 thus resulting in irreversible inhibition of these enzymes. Other NSAIDs are reversible, competitive inhibitors of cyclooxygenases.
Because aspirin and other NSAIDs are organic acids and have a high capacity to bind to proteins, they accumulate in inflamed tissues, the GI mucosa, the renal cortex, the blood and in the bone marrow. These facts are well known and can be found in textbooks of Pharmacology such as Goodmann and Gilman's Pharmacological Basis Of Therapeutics, McGraw-Hill, New York
Aspirin is rapidly deacetylated by the liver. However, COX-1 in platelets can be inhibited by low doses of aspirin in the portal circulation, thereby sparing COX-1 in endothelial cells and prostacylin synthesis (Benett 2001). NSAIDs are the most widely used drugs in the world; about 70 million people each day take prescribed NSAIDs, and about 200 million people each day take over-the-counter NSAIDs (Smith T. G. Rheum. Dis. Clin. North Am. 1998, 24, 501–523). In the United States 80 billion aspirin tablets are consumed annually (Flieger K. FDA Consum. January–February 1994) and about 50 million people spend $5–10 billion on NSAIDs each year (DuBois R. N. et al FASEB J. 1998, 12, 1063). Since the determination of these figures in 1999, it is most likely that the use of NSAIDs has further increased. Population studies have shown that 10–20% of all people who are 65 years or older are either currently receiving or have recently received a prescription for a nonsteroidal anti-inflammatory drug. During the next 20 years the number of people over 65 is expected to increase from 380 million to 600 million.
The frequent use of NSAIDs is based on the fact that it has many indications including mild headache, menstrual pain, fever, chronic polyarthritis, psoriatic arthritis, ankylosing spondylitis, osteoarthritis, gout, inflammatory soft tissue rheumatis, low back pain, postoperative and post-traumatic inflammation, thrombophlebitis and vasculitis (Juergen Steinmeyer, 2000, Arthritis Research 2, 379–385). In addition to the traditional use for the above indications, NSAIDs have been shown to be effective in the prevention of vascular disorders. Aspirin is the most widely used inhibitor of platelet function and is the standard against which other agents are judged. In the Antiplatelet Trialist Collaboration (46 trials with patients with acute myocardial infarction, prior myocardial infarction, unstable angina, stroke, or transient ischemic attack, aspirin reduced the long term risk of recurrent infarction, stroke, or death from a vascular cause by 25%. Aspirin acetylates COX-1 not only in platelets, but also in endothelial cells thereby preventing the synthesis of prostacyclin, a potent vasodilatator and platelet inhibitor. Despite the inhibition of prostacyclin, aspirin has a net anti-platelet effect by inhibiting thromboxane A2 synthesis in platelets (Benett 2001).
Not all biological effects of NSAIDs are related to the inhibition of cyclooxygenases. Other potential targets include nuclear receptors such as peroxisome proliferator activated receptor gamma and delta (PPAR γ and δ), kinases such as 1 kb kinase (IKKβ), and certain phosphodiesterases such as PDE5 and 2. Interactions of NSAIDs with such target depends on the structure and dose of the compound, and may have beneficial or adverse consequences.
NSAIDs are generally well tolerated; however, adverse reactions do occur in a small but important percentage of patients. Because of the very extensive use of NSAIDs this results in substantial morbidity and mortality. The most serious side effect of aspirin and related NSAIDs are gastrointestinal disorders, in particular the induction of gastroduodenal ulcers. Long term administration of aspirin also leads to a small increase in the number of hemorrhagic strokes. There is a dose dependent relationship to both complications. They can be minimized, but not eliminated, by administering the lowest effective dose of aspirin. The annual number of hospitalizations in the United States for serious gastrointestinal complications of NSAID use is at least 100,000 and the annual direct costs of such complications exceed U.S. $2 billion. The mortality rate among patients who are hospitalized for NSAID induced upper gastrointestinal bleeding is about 5 to 10% (for references to original articles see Wolke M. M., Lichtenstein D. R. and G. Singh, 1999; The New England Journal of Medicine 340, 1888–1899).
Extensive efforts have been made to prevent the adverse effects of NSAIDs. One strategy which has proven to be effective is to supplement NSAIDs medication with protective prostaglandin derivatives, such as misoprostol, or with a proton pump inhibitor, such as ranitidine. Another strategy is to modify NSAIDs themselves either to make them more selective or to add protective moieties. Safer NSAIDs have been developed, which selectively inhibit only the inducible cyclooxygenase, COX-2. The increased safety profile of selective COX-2 inhibitors is thought to be due to the fact that prostaglandins generated by COX-2 at the sites of injury cause tissue swelling, pain and inflammation, while those generated by COX-1 in the mucosa and by platelets have protective functions. Two selective COX-2 inhibitors, celcoxib (Celebrex®) and rofecoxib (Vioxx®) have become available and several related compounds are in early clinical development. Celecoxib and rofecoxib maintain selectivity for COX-2 even at high doses. It has been demonstrated in several clinical trials that these novel NSAIDs do cause less gastrointestinal complications than nonselective COX inhibitors.
Recent studies have shown that selective COX-2 inhibitors might open up a wide spectrum of new indications for NSAIDs. The degeneration of large areas of the brain in Alzheimer's disease is supposed to occur with the involvement of COX-2. Selective COX-2 inhibitors might also be directed towards the therapy of colorectal carcinomas. COX-2 expression is also increased in gastric and breast carcinomas, suggesting that selective COX-2 inhibitors might also be therapeutically useful for treating those tumours. Recently the US FDA approved the selective COX-2 inhibitor celecoxib for the treatment of the rare genetic disorder called familial adenomatous polyposis. Animal experiments have shown that COX-2 inhibitors inhibit angiogenesis and tumour growth in a dose dependent manner. COX-2 is expressed in the newly created blood vessels (especially in the endothelial cells) needed for tumour growth.
The advent of COX-2 selective compounds has motivated scientists to revisit the physiological and pathological role of the two known cyclooxygenase isozymes. These studies have revealed several potential disadvantages of cyclooxygenase inhibitors in general, and of selective COX-2 inhibitors in particular. While selective COX-2 inhibitors are effective in preventing colon cancer and possibly Alzheimers disease (Tocco G., Freire-Moar J. and Schreiber S. S.; 1997, Exp. Neurol 144, 339), they do not provide the prophylactic benefits of aspirin in vascular disease, which is largely, if not exclusively based on the reduction of COX-1 mediated thromboxane A2 synthesis in platelets. COX-2 was shown to have not only pro- but also anti-inflammatory properties (reviewed by P. R Colville-Nash and D. W. Gilroy; 2001, BioDrugs 15,1–9). In a crageenan induced pleurisy model in rats COX-2 first generated PGE2, which increased the transactivation function of NFkB and thereby upregulated the expression of many inflammatory mediators. At a later time point a shift occurred in which, by unknown mechanisms, PGE2 production was down regulated, while the production of cyclopentenone prostaglandins was increased. The “late” prostaglandins, which include PGD2 and its derivatives, in particular PGJ2, inhibit inflammation, at least in part by inhibiting NFkB signal transduction (A. Rossi, P. Kapahi, G. Natoli, T. Takahashi, Y. Chen, M. Karin and M. G. Saunter; 2000, Nature 403, 103–108). These findings indicate that cycloxygenase inhibitors may delay the resolution of inflammation (see B. Poligone and A. S. Baldwin; 2001, The Journal of Biological Chemistry 276, 38658–64). Indeed cyclooxygenase inhibitors have been shown to delay gastric ulcer healing in mice (H. Mizunonet; 1997, Gastroeneterology 112, 387–397) and to exacerbate induced colitis in rats (A. Schmassmann, B. M. Peskar, C. Stettler, et al; 1998, Br. J. Pharmacology 123, 795–804; M. N. Ajuebor, A. Singh, and J. L. Wallace; 2000, Am J. Physiol. Gastrointest Liver Physiol 279, G238–44). In some patients treated with selective COX-2 inhibitors ulcers have progressed further to perforation.
A more recent study suggests that COX-2 mediated prostaglandin production is required for the generation of TGFβ producing regulatory T cells that mediate oral tolerance to dietary antigens (for references see 0. Morteau; 1999, Nature Medicine 5, 867–8). Sugawa and colleagues pointed out that COX-2 inhibitors may increase the production of leukotrienes, such as leukotriene B4 (LTB4), which is one of the most potent chemotactic/inflammatory factors (K. Sugawa, T. Uz, V. Kumar and H. Manev; 2000, Jpn J Pharmacol 82, 85). In chronically inflamed pulmonary tissue, NSAIDs lead to an increased production of leukotrienes and in this way to asthma-like reactions due to the inhibition of prostaglandin synthesis. COX-2 has also been reported to be involved in the regulation of the renin-angiotensin system, and to possess vasoactive anti-atherogenic properties (G. Dannhardt and W. Kiefer; 2001, European Journal of Medicinal Chemistry 36, 109–126). Based on these findings, COX-2 inhibitors might be expected to delay the resolution of inflammatory lesions and to exacerbate hypertension and atherocleosis. Thus, selective COX-2 inhibition is likely not to be the final triumph of the search for improved version of sodium salicylate, which began more than 100 years ago.
Another strategy to reduce the side effects of aspirin and aspirin-like drugs has been the attachment of NSAIDs with protective compounds. At least part of the toxicity of NSAIDs has been ascribed to their ability to bind to zwitterionic phospholipids, which provide the mucus gel layer with non-wettable properties. Preassociating NSAIDs with exogenous zwitterionic phospholipids prevented them from increasing the wettability of the mucus gel layer and protected rats against the injurious gastrointestinal side effects of these drugs, while enhancing their lipid permeability, anti-pyretic and anti-inflammatory activity (L. M. Lichtenberg, Z. M. Wang, J. J. Romero, C. Ulloa, J. C. Rerez, M. N. Giraud and J. C. Baretto, 1995, Nat Medicine 1, 154).
Another approach, which is currently in clinical testing, utilizes NSAIDs that are covalently derivatized with a nitric oxide (NO) releasing moiety (NO-NSAIDs). This strategy, which has been described in a series of patents (U.S. Pat. Nos. 5,621,100; 5,700,947; 5,861,426; 6,040,341; 6,218,417 B1; 6,218,417 B1; and 6,242,432) is based on the observation, that, NO has cytoprotective properties. In particular in the stomach, NO exhibits many of the same actions as prostaglandins, such as stimulation of mucus secretion and maintenance of mucosal blood flow. Indeed, NO-NSAIDs did not cause any gastrointestinal injuries in animals, and exhibited anti-inflammatory and analgesic effects, which exceeded those of the parent compounds (for references see P. del Soldato, R. Sorrentino and A. Pinto; 1999, Trends I Pharmacological Science 20, 319). The NO release from these compounds is a metabolic rather than a spontaneous process. The anti-inflammatory effects of these compounds are thought to be due in part to the inhibition of cyclooxygenases, and in part to the nitrosation and inactivation of caspase 1, an enzyme, that is required for the generation of at least two inflammation promoting cytokines, interleukin 1 and interleukin 18 (S. Fiorucci; 2001, Trends in Immunology 22, 232–235). Clinical studies must be undertaken to compare NO-NSAIDs and their parent drugs with regard to safety profile and therapeutic efficacy.
In contrast to COX-2 inhibitors nitro-aspirin is expected to retain or even surmount the prophylactic effect of aspirin in cardiovascular disease. One of the nitro-aspirin compounds, referred to as NC4016, inhibited arachidonic acid—stimulated aggregation of platelets at a concentration of 100 μM, whereas aspirin induced the same effect at 10 μM. However NC4016 was more efficient than aspirin in inhibiting platelet aggregation and adhesion induced by thrombin. The antithrombotic effect of NC4016 appears to be due at least in part to the release of NO, which results in increased cGMP levels in platelets, as well as to the inhibition of prostanoid synthesis.
Many diverse effects have been ascribed to endogenously produced NO and to therapeutically administered NO or NO donors. These include regulation of blood flow, maintenance of vascular tone, control of platelet aggregation, and various roles in the central and peripheral nervous system. The phenomenology described in the literature is rather complex. NO has been reported to have either pro- or anti-inflammatory effects (H. Kolb and V. Kolb-Bachofen; 1998, Immunology Today 19, 556) and pro- or anti-atherogenic effects (R. P. Patel, A. Levonen, J. H. Crawford, and V. M. Darley-smar; 2000, Cardiovascular Research 47, 465–74). Therefore, it is difficult to predict the long term effects of compounds, which exhibit sustained NO release.
There exists a need in the art for methods for preventing and/or treating diseases, for example, inflammatory diseases. In addition, there is a need for compounds and pharmaceutical compositions for preventing and/or treating diseases, for example, inflammatory diseases.